Real-World Long-Term Musculoskeletal and Extra-Skeletal Outcomes of Obesity, Diabetes, Ageing, Frailty, and Sarcopenia: The Oswestry Metabolic BONE Cohort

The overarching aim of this study is to look at the longitudinal musculoskeletal and extra-skeletal health outcomes for patients at risk for fracture who are attending the RJAH metabolic bone service as standard of care. This work is designed to use data collected as standard of care as well as research specific data. Standard of care data, which is anonymised before analysis is covered by existing ethics (22/PR/0076). However, the researchers will seek to consent patients for access to their medical records held by their GP. This is due to the importance of having accurate and reliable data on a patient's medical history for both clinical decisions and research studies pertaining to bone health. Data obtained from standard of care, relevant medical history, biological samples, and diagnostic imaging will be analysed to provide a holistic approach to understanding why patients fracture and how best to predict future fracture risk and identify parameters of treatment response. This research will assess the well-established traditional risk factors for fracture and explore novel risk factors related to chronic conditions such as diabetes, obesity, sarcopenia, and frailty as well as novel biomarkers including 'omics' (metabolomics, proteomics) and the microbiome, to understand how the gut microbiome influences bone health and to reveal new pathological and mechanistic metabolic pathways.

It is widely known that different lifestyle factors can have a huge impact on health. Smoking, excessive alcohol intake, poor diet and lack of exercise increase the chances of developing a range of diseases, osteoporosis being one of them. The increased body weight in obesity has been consistently shown to be associated with a higher BMD measured by dual energy X-ray absorptiometry (DXA)20 but despite the improved BMD, obese patients may have higher incidence of fracture, a phenomenon known as "obesity paradox". In routine practice, the fracture frisk is calculated using the FRAX® tool which considers high body mass index (BMI) as a protective factor for fracture. As a result, many obese patients with fracture are denied anti-osteoporosis treatment because they do not have a BMD low enough to qualify for treatment with FRAX score falling below the treatment threshold according to the UK National Osteoporosis Guideline Group (NOGG 2021).

Chronic conditions such as obesity and diabetes have been linked with an increased fracture risk, but it is unknown whether the combination of these two conditions, termed 'diabesity', carries a higher fracture risk compared to having obesity or diabetes alone. Further research to improve our understanding of these risk factors and optimise the management of osteoporosis is urgently needed and will form part of this body of research work. Metabolomics offers great potential to unlock complex pathways involved in metabolic processes, which could identify biomarkers associated with osteoporosis. This could help in the early detection, diagnosis, and monitoring of disease progression. Building a biobank of blood, plasma and serum samples from consenting patients will allow us to conduct a number of 'omics' and other high content studies, which will ultimately help us to understand disease mechanisms by looking at the interaction of proteins, genes and metabolites.

Microbiome studies also offer a huge beneficial research potential. The gut microbiome (GM) is the community of trillions of microorganisms (bacteria, viruses, fungi, and other microbes) that live in the gastrointestinal tract. These microorganisms perform essential functions, including aiding digestion and metabolism, synthesising vitamins, regulating immune responses and inflammation, and protecting against pathogens.

An increasingly emerging concept of the gut-bone axis refers to the complex communication pathways between the GM and bone metabolism. When the GM is imbalanced (dysbiosis), it can lead to increased inflammation and oxidative stress, both of which are detrimental to bone health. Dysbiosis can cause: